Trifluoromethylhydroxybenzoic acids and their group i metal salts



3,052,603 TRIFLUOROME 2 I HYDROXYBENZOIC ACIDS AND THEE GROUP I METALSALTS Murray Hauptschein, Glenside, Pa., assignor to Pennsalt ChemicalsCorporation, Philadelphia, Pa., a corporation of Pennsylvania NoDrawing. Filed May 15, 1958, Ser. No. 735,647 9 Claims. (Cl. 167-58)This invention rel-ates to derivatives of hydroxybenzoic acids.Particularly it relates to compounds represented by the formula OFs OOOY

. pounds, e.g. dicarboxylic acids or azo dyes.

This application is a continuation-in-part of copending applicationSerial No. 447,390, filed August 2, 1954.

The novel compounds of this invention are prepared by various methods,most of them previously known. 4-trifluoromethyl-6-hydroxybenzoic acid,hereinafter referred to as 4-trifluoromethylsalicylic acid, is preparedby the method disclosed and claimed in U.S. 2,894,984, also derived fromsaid Serial No. 447, 390. The method comprises direct carboxylation ofm-trifluoromethylphenol with carbon dioxide and an alkali metalcarbonate under pressure at a temperature in the range from about 20 C.to about 250 C. followed by acidification of the reaction mass accordingto the following equation, wherein M is Na, Li, or K:

or. or, or,

M2003 HCl on OH on The preparation of 4-trifluoromethy1salicylic acidand its properties and structure are more fully disclosed in thefollowing example.

EXAMPLE 1 Preparation of 4-Triflu0romethylsalicylic Acidm-Trifluoromethylphenol (48.6 g.) and granular anhydrous potassiumcarbonate (124.4 g.) were intimately dispersed in a copper bomb of 250ml. capacity, and carbon dioxide gas from a commercial cylinder wasintroduced at 300 p.s.i. at room temperature. The temperature wasallowed to rise very slowly over a period of ten days to 220 C. It wasnoted that some carbon dioxide was absorbed even at room temperature andat 140 C. the reaction was nearly completed. As the carbon dioxide wastaken up, additional gas was introduced. At the completion of thereaction the bomb was cooled, vented, and

opened. The product was a hard cake of potassium-4-trifluorornethylsalicylate. The cake was dissolved in hot United StatesPatent M 3,052,603 Patented Sept. 4, 1962 water. The solution wasextracted with ether, neutralized to a pH of about 6, decolorized withcharcoal and filtered. The filtrate was acidified with concentratedhydrochloric acid. An 88% yield of 4-trifluoromethylsalicylic acid wasobtained. No isomers were found present, and only a trace of unreactedphenol was detected in the product. On recrystallization from alcoholand water, the 4-trifluoromethylsalicylic acid was found to melt at178178.5 C. (white needles).

Analysis.-Calcd. for C H C F C, 46.61; H, 2.45; mol. wt. 206. Found: C,46.55; H, 2.46; mol. wt. (neut. eq.), 208.

4-trifluoromethylsalicylic acid is miscible with ethanol but only veryslightly soluble in water.

Crystalline 4-trifiuoromethylsalicylic acid (0.80 g.) made by the abovemethod was heated in a Pyrex tube on a Bunsen flame with 6 ml. ofconcentrated sulfuric acid. The solution turned deep brown and hydrogenfluoride fumes were liberated. After pouring the reaction mass intoice-water and recrystallizing the resultant precipitate with alcohol andwater, there was isolated 0.60 g. of the known Z-hydroxyterephthalicacid (M.P. 327 C.; dimethyl ester, M.P. 93-94 C.; recrystallized fromalcohol), thus proving the structure to be that of4-trifluoromethylsalicylic acid.

The preparations and properties of 2-trifluoromethyl-4- hydroxybenzoicacid, which has the formula OOOH and of3-trifluoron1ethyl-S-hydroxybenzoic acid, which has the formula CFg aredisclosed in the following examples.

EXAMPLE 2 Preparation of 2-Triflu0r0methyl-4-Hydr0xybenzoic Acid2-trifluoromethyl-4-nitroaniline was converted into 2-trifiuoromethyl-4-nitrobenzonitrile via the Sandmeyer reaction usingpotassium nickelocyanide in 32.5% yield. It melted at 48-49.5 C.(recrystallized from 20% aqueous alcohol).

Analysis.-Calcd. for C H O N F C, 44.46; H, 1.40; N, 12.96. Found: C,44.73; H, 1.32; N, 12.90.

Two and seven-tenths grams of said 2-trifiuoromethy1-4-nitrobenzonitrile in 25 ml. of 63% sulfuric acid were heated slowly to182 C. and kept at that temperature for half an hour. The cooledsolution was thrown on ice and there were collected 2.6 g. (92%) ofZ-trifluoromethyl-4-nitrobenzoic acid M.P. 137l40 C. A singlerecrystallization from water gave white platelets, M.P. 138.5-140" C.

Analysis.-Calcd. for C H O F N: C, 40.86; H, 1.71; N, 5.96. Found: C,40.77; H, 1.61; N, 6.15.

When 75% sulfuric acid was used, 4-nitrophthalic acid was formed, due tohydrolysis of the trifluorornethyl group, while 55-60% sulfuric acidyielded some of the amide due to incomplete hydrolysis of the nitrile.

'Reduction of said 2-trifiuorornethyl-4-nitrobenzoic acid with iron andammonium chloride gave white crystals of4-amino-2-trifluoron1ethylbenzoic acid, M.P. 1855-187 C. in 75 yield.

Analysis.Calcd. for C H O NF C, 46.84; H, 2.95; N, 6.83. Found: C,46.85; H, 2.94; N, 6.93.

Eighty-two hundredths gram of said 4-amino-2-trifiuoromethylbenzoic acidwas dissolved in a solution of 4 ml. of concentrated sulfuric acid and20 ml. of water, and was diazotized with 0.28 g. of sodium nitrite in 4ml. of water. The diazonium solution was then added in portions to arefluxing solution of 4 ml. of concentrated sulfuric acid in 32 ml. ofwater and heated for one hour. After cooling and extracting with etherthere was isolated 0.7 g. of crude material which melted below 100 C.and probably contained much water of hydration. After arecrystallization from benzene the product melted at 150l53.5 C. (0.5 g.61%). Two additional recrystallizations from benzene afforded pure whiteZ-trifluoromethyl-4-hydroxybenzoic acid, M.P. 152.5154 C.

Analysis.-Calcd. for C H O F C, 46.61; H. 2.45. Found: C, 46.78; H,2.75.

EXAMPLE 3 Preparation of 3-Triflu0romethyl-S-Hydroxybenzoic Acidm-Trifluoromethylbenzoic acid was prepared in high yield by the reactionof the Grignard reaction products of m-bromoand m-iodobenzotrifluori'dewith carbon dioxide. Eighty-one grams of this acid, M.P. 103104 C., wereadded with stirring to 500 g. of fuming sulfuric acid. Nitric acid (90%sp. gr. 1.5, 125 g.) was introduced gradually to the mixture withefiicient stirring, the temperature being maintained below 70 C. Thereaction mixture was heated on a water bath for an additional 4-5 hoursand then poured upon crushed ice, filtered, washed thoroughly withwater, and dried at 70 C. There were isolated 90 g. (90%) of the white3-trifluoromethyl-5- nitrobenzoic acid, M.P. l27-129 C.; recrystallizedfrom water, M.P. l28l29 C.

Analysis.-Calcd. for C H O NF C, 40.86; H, 1.71; N, 5.96. Found: C,41.01; H, 1.78; N, 6.04, 5.94.

Thirty-five grams of said 3-trifluoromethyl-5-nitrobenzoic acid wereadded in portions to a stirred mixture of 48 g. of iron powder and asolution of 24.5 g. of ammonium chloride in 400 ml. of water at 50 C.The mixture was refluxed with stirring for three hours, during whichtime so much foaming was encountered that it was necessary to replacethe 2 liter reaction flask with a 3 liter one. The mixture was thentreated with 10% sodium carbonate, filtered, and neutralized withconcentrated hydrochloric acid. The solution was allowed to standovernight. 21.6 g. of precipitate formed. This crude prodnot wasredissolved and reprecipitated with acid. There was isolated 16.7 g.(55%) of white 3-amino-5-trifluoromethylbenzoic acid, M.P. 141-1425 C.

Analysis.Calcd. for C H O NF C, 46.84; H, 2.95; N, 6.83. Found: C,46.72; H, 3.23; N, 6.89, 6.72.

One gram of said 3-amino-5-trifluoromethylenzoic acid was diazot-ized insulfuric acid and then hydrolyzed essentially as described previouslyaffording 0.6 g. (60%) of white 3-trifluoromethyl 5 hydroxybenzoic acid,M.P. 191.5192.5 C. (decolorized and recrystallized from hot water).

Analysis.-Calcd. for C H O F C, 46.61; H, 2.45. Found: C, 46.87; H,2.79.

The structure of 2-trifluoromethyl-4-hydroxybenzoic acid and of3-trifluoromethyl-5-hydroxybenzoic acid is readily confirmed byconverting each to its corresponding dicarboxylic acid in the mannerdescribed above for the 4- trifluoromethylsalicylic acid compound. Theresulting dicarboxylic acids are useful reactants with polyhydricalcohols to form polyester resins and plastics, often called alkydresins, useful in the manufacture of paints and varnish.

The novel trifluoromethylhydroxybenzoic acid of this invention arereadily converted to trifluoromethylhydroxybenzoates of group I metalsand are especially useful in this new form in fungicidal applications.It is to be noted that the acid compound is the active material auditsactivity is effective whether it is used as such or in the form of asalt. The change at the carboxyl group of the acid is a mere change inform and not in essential character.

The metal salts of said trifiuoromethylhydroxybenzoic acids are preparedby reacting acids with a water-soluble inorganic salt of a metalselected from group I of the periodic table of elements, in particularthe carbonate or bicarbonate of lithium, sodium or potassium and thenitrate or chloride of copper, rubidium, silver, cesium or gold. Thepreparation of said metal salts is shown in the following exampleswherein 4-trifluoromethylsalicylic acid(4-trifluoromethyl-6-hydroxybenzoic acid) is used by way of example ofone of the trifiuoromethylhydroxybenzoic acids of this invention.

EXAMPLE 4 Preparation of Silver-4-Trifluor0methylsalicylate4-trifluoromethylsalicylic acid is neutralized with aqueous ammonia andreacted with silver nitrate solution to give a quantitative yield ofsilver-4-trifluoromethylsalicylate, which precipitates from thesolution.

Analysis.Calcd. for C H O F Ag: Ag, 34.47. Found: Ag, 34.27.

EXAMPLE 5 Preparation of Caprous-l-Trifluoromethylsalicylate4-trifluoromethylsalicylic acid is neutralized with aqueous ammonia andreacted with cuprous chloride solution to givecuprous-4-trifluoromethylsalicylate in the form of a precipitate.

EXAMPLE 6 Preparation of Cupric-Bis(4-Trifluor0methylsalicylate)4-trifluoromethylsalicylic acid is neutralized with aqueous ammonia andreacted with cupric chloride solution to givecupric-bis(4-trifluoromethylsalicylate) in the form of a precipitate.

EXAMPLE 7 Preparation of Sodiam-4-TriflaoromethylsalicylateSodium-4-trifluoromethylsalicylate is prepared by dissolving4-trifluoromethylsalicylic acid in 10% sodium carbonate solution,cooling in ice, and collecting the salt formed. It is a white solidwhich is soluble in water.

EXAMPLE 8 Preparation of Lithium-4-Trifluor0methylsalicylate4-trifluoromethylsalicylic acid is dissolved in 5% lithium bicarbonatesolution, with ice cooling. Lithium-4-trifiuoromethylsalicylate formsand precipitates from the solution.

EXAMPLE 9 Preparation of Potassium-4-TrifluoromethylsalicylateRubidium-4-trifluoromethylsalicylate,Cesium-4-trifiuoromethylsalicylate,Auric-tris(4-trifluoromethylsalicylate) and Aurous-4trifiuoromethylsalicylate.

The group I metal salts of 2-trifluoromethyl-4-hydroxybenzoic acid andof 3-trifluoromethyl-5-hydroxybenzoic acid can be prepared bysubstituting the respective ac1ds Potassium- EXAMPLE 10 A 5% solution of4-t1'ifiuoromethylsalicylic acid in propylene glycol 200 (M.W.) wasprepared and used in control of the growth of T. mentagrophytes oninfected scales. Salicylic acid was used for comparison of the relativeactivity with a diluent control sample. The data and results are shownin Table I where +=growth and O=no growth.

TABLE I Exposure Time Concentration of Compound 5 min. 15 min. 30 min. 1hr.

5% Trifluoromethylsalicylio a 'd 0 O Salicylic acid 0 0 Diluent ControlScales Growth Control From the test results it will be noted that4-trifluoromethylsalicyl-ic acid has definite antifungal activity,killing the organism with 5 to 15 minutes exposure time. It is alsoshown to be superior to salicylic acid in this property.

EXAMPLE 11 A beneficial powder for treatment of ringworm of the feet isprepared by mixing together five parts of 4-trifluoromethylsalicylicacid, two parts of menthol, eight parts of camphor, 50 parts of boricacid and 35 parts of starch.

2-trifluoromethyl-4-hydroxybenzoic acid and3-trifluoromethyl-S-hydroxybenzoic acid and any of the group I metalsalts of them, or of 4-trifluoromethylsalicylic acid, can each beformulated individually or in admixture into fungicidal compositionsuseful in said ringworm treatment by substituting each or a mixture ofthem for 4-trifluoromethylsalicylic acid in the composition disclosed inExample 11.

Z-trifluoromethyl 4 hydroxybenzoic acid, and 4-trifluoromethylsa-licylicacid and 3-trifluoromethyl 5 hydroxybenzoic acid are also each useful aschemical intermediates for coupling with negatively substituteddiazotized amines to form dye compounds, as disclosed and claimed incopending application Serial No. 735,644, filed May 15, 8.

The above/described embodiments of the invention are presented for thepurpose of illustration. Many widely different embodiments of thisinvention can be made without departing from the spirit and scopethereof, and it is to be understood that the invention is not intendedto be limited by the above-noted specific embodiments.

I claim:

1. A process for controlling fungus disease of the epidermis by applyingthereto a fungicidal amount of a mixture comprising a carrier and acompound selected from the group consisting of2-trifluoromethyl-4-hydroxybenzoic acid,3-trifluoromethyl-5-hydroxybenzoic acid,4-trifluoromethyl-6-hy-droxybenzoic acid and group I metal salts of eachof said acids.

2. As a fungicidal keratolytic composition, a mixture comprising acarrier and a compound selected from the group consisting ofZ-trifluoromethyl-4-hydroxybenzoic acid,3-trifluoromethyl-S-hydroxybenzoic acid,4-trifluoromethyl-6-hydroxybenzoic acid and group I metal salts of eachof said acids.

3. The composition according to claim 2 wherein the carrier is afinely-divided solid.

4. As a fungicidal keratolytic composition, a mixture comprising4-trifluoromethylsalicylic acid dispersed with a finely-divided solidcarrier.

5. A compound selected from the group consisting ofZ-trifluoromethyl-4-hydroxybenzoic acid,3-trifluoromethyl-S-hydroxybenzoic acid, 4-trifluoromethyl-6hydroxybenzoic acid and group I metal salts of each of said acids.

6. Z-triflnoromethyl-4-hydroxybenzoic acid.

7. 3-trifiuoromethyl-5-hydroxybenzoic acid.

8. 4-trifluoromethylsalicylic acid.

9. Silver-4-trifluoromethylsalicylate.

References Cited in the file of this patent UNITED STATES PATENTS2,114,369 Bickenheuser Apr. 19, 1938 2,244,769 Dcelling June 10, 19412,576,987 Wyman Dec. 4, 1951 2,685,600 Morris Aug. 3, 1954 2,731,386Reiner Jan. 17, 1956 2,821,551 Katzschmann Jan. 28, 1958 2,894,984Hauptschein July 14, 1959

1. A PROCESS FOR CONTROLLING FUNGUS DISEASE OF THE EPIDERMIS BY APPLYINGTHERETO A FUNGICIDAL AMOUNT OF A MIXTURE COMPRISING A CARRIER AND ACOMPOUND SELECTED FROM THE GROUP CONSISTING OF2-TRIFLUOROMETHYL-4-HYDROXYBENZOIC ACID,3-TRIFLUOROMETHYL-5-HYDROXYBENZOIC ACID,4-TRIFLUOROMETHYL-6-HYDROXYBENZOIC ACID AND GROUP I METAL SALTS OF EACHOF SAID ACIDS.